The emergent relationship between temporoparietal junction and anosognosia in Alzheimer's disease.

Anosognosia and impairment of insight are characteristic features of Alzheimer's disease (AD), which can lead to delays in appropriate medical care and significant family discord. The default mode network (DMN), a distributed but highly connected network of brain regions more active during rest than during task, is integrally involved in awareness. DMN dysfunction is common in AD, and disrupted communication between memory-related and self-related DMN networks is associated with anosognosia in AD patients. In addition, the temporoparietal junction (TPJ) is a key region of the "social brain" and also contributes to representations of the self. The exact classification of the TPJ within the DMN is unclear, though connections between the TPJ and DMN have been highlighted in multiple avenues of research. Here we discuss the relationship between the TPJ, DMN, and AD, as well as the potential involvement of the TPJ in anosognosia in AD. We review past and present findings to raise attention to the TPJ, with a specific emphasis on neuroimaging technologies which suggest a pivotal role of the TPJ within large-scale brain networks linked to anosognosia in AD.

Hippocampal diaschisis contributes to anosognosia for hemiplegia: Evidence from lesion network-symptom-mapping.

Anosognosia for hemiplegia (AHP) is known to be associated with lesions to the motor system combined with varying lesions to the right insula, premotor cortex, parietal lobe or hippocampus. Due to this widespread cortical lesion distribution, AHP can be understood best as a network disorder. We used lesion maps and behavioral data (n â€‹= â€‹49) from two previous studies on AHP and performed a lesion network-symptom-mapping (LNSM) analysis. This new approach permits the identification of relationships between behavior and regions connected to the lesion site based on normative functional connectome data. In a first step, using ordinary voxel-based lesion-symptom mapping, we found an association of AHP with lesions in the right posterior insula. This is in accordance with previous studies. Applying LNSM, we were able to additionally identify a region in the right posterior hippocampus where AHP was associated with significantly higher normative lesion connectivity. Notably, this region was spared by infarction in all patients. We therefore argue that remote neuronal dysfunction caused by disrupted functional connections between the lesion site and the hippocampus (i.e. diaschisis) contributed to the phenotype of AHP. An indirect affection of the hippocampus may lead to memory deficits which, in turn, impair the stable encoding of updated beliefs on the bodily state thus contributing to the multifactorial phenomenon of AHP.

Anosognosia and default mode subnetwork dysfunction in Alzheimer's disease.

Research on the neural correlates of anosognosia in Alzheimer's disease varied according to methods and objectives: they compared different measures, used diverse neuroimaging modalities, explored connectivity between brain networks, addressed the role of specific brain regions or tried to give support to theoretical models of unawareness. We used resting-state fMRI connectivity with two different seed regions and two measures of anosognosia in different patient samples to investigate consistent modifications of default mode subnetworks and we aligned the results with the Cognitive Awareness Model. In a first study, patients and their relatives were presented with the Memory Awareness Rating Scale. Anosognosia was measured as a patient-relative discrepancy score and connectivity was investigated with a parahippocampal seed. In a second study, anosognosia was measured in patients with brain amyloid (taken as a disease biomarker) by comparing self-reported rating with memory performance, and connectivity was examined with a hippocampal seed. In both studies, anosognosia was consistently related to disconnection within the medial temporal subsystem of the default mode network, subserving episodic memory processes. Importantly, scores were also related to disconnection between the medial temporal and both the core subsystem (participating to self-reflection) and the dorsomedial subsystem of the default mode network (the middle temporal gyrus that might subserve a personal database in the second study). We suggest that disparity in connectivity within and between subsystems of the default mode network may reflect impaired functioning of pathways in cognitive models of awareness.

Functional Neural Correlates of Anosognosia in Mild Cognitive Impairment and Alzheimer's Disease: a Systematic Review.

Functional neuroimaging techniques (i.e. single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging) have been used to assess the neural correlates of anosognosia in mild cognitive impairment (MCI) and Alzheimer's disease (AD). A systematic review of this literature was performed, following the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement, on PubMed, EMBASE, and PsycINFO databases. Twenty-five articles met all inclusion criteria. Specifically, four brain connectivity and 21 brain perfusion, metabolism, and activation articles. Anosognosia is associated in MCI with frontal lobe and cortical midline regional dysfunction (reduced perfusion and activation), and with reduced parietotemporal metabolism. Reduced within and between network connectivity is observed in the default mode network regions of AD patients with anosognosia compared to AD patients without anosognosia and controls. During initial stages of cognitive decline in anosognosia, reduced indirect neural activity (i.e. perfusion, metabolism, and activation) is associated with the cortical midline regions, followed by the parietotemporal structures in later stages and culminating in frontotemporal dysfunction. Although the current evidence suggests differences in activation between AD or MCI patients with anosognosia and healthy controls, more evidence is needed exploring the differences between MCI and AD patients with and without anosognosia using resting state and task related paradigms.

Functional connectivity and the failure to retrieve meaning from shape in visual object agnosia.

The neural mechanisms underlying the access to object knowledge from early representations of shape are little known. Functional imaging studies support the view that representations of visual properties are distributed across occipito-temporal cortex of both cerebral hemispheres. By contrast, brain lesion studies show that focal occipito-temporal damage may lead to object agnosia - a specific impairment of object recognition. How does distributed processing fit with functional specialization implied by the existence of stimulus-specific agnosias? Using fMRI we studied functional connectivity (FC) in a patient with object agnosia following left lateral occipital damage. Despite intact global and local processing of 2D and 3D object structure, the patient made consistent object identification errors. Seven experiments testing naming, visual matching or object priming showed that his errors mainly reflected the global shape similarity between objects. Compared to controls the patient exhibited strongly reduced FC between the damaged left and the intact right medial/lateral occipital cortex. In addition, controls showed stronger connectivity between the right occipital cortex and the left and right inferior and anterior temporal cortices. Interestingly, the patient also showed compensatory increases of FC between dorsal occipital and medial parietal cortex. These findings show that focal damage to the lateral occipital cortex may have global effects on representations of objects in bilateral occipito-temporal cortex, thus supporting the view that bilaterally distributed coding is necessary for the retrieval of associative knowledge from shape.

Preserved Expert Object Recognition in a Case of Visual Hemiagnosia.

We examined a stroke patient (HWS) with a unilateral lesion of the right medial ventral visual stream, involving the right fusiform and parahippocampal gyri. In a number of object recognition tests with lateralized presentations of target stimuli, HWS showed significant symptoms of hemiagnosia with contralesional recognition deficits for everyday objects. We further explored the patient's capacities of visual expertise that were acquired before the current perceptual impairment became effective. We confronted him with objects he was an expert for already before stroke onset and compared this performance with the recognition of familiar everyday objects. HWS was able to identify significantly more of the specific ("expert") than of the everyday objects on the affected contralesional side. This observation of better expert object recognition in visual hemiagnosia allows for several interpretations. The results may be caused by enhanced information processing for expert objects in the ventral system in the affected or the intact hemisphere. Expert knowledge could trigger top-down mechanisms supporting object recognition despite of impaired basic functions of object processing. More importantly, the current work demonstrates that top-down mechanisms of visual expertise influence object recognition at an early stage, probably before visual object information propagates to modules of higher object recognition. Because HWS showed a lesion to the fusiform gyrus and spared capacities of expert object recognition, the current study emphasizes possible contributions of areas outside the ventral stream to visual expertise.

Asymmetric oculomotor apraxia, optic ataxia, and simultanagnosia with right hemispatial neglect from a predominantly left-sided lesion of the parieto-occipital area.

INTRODUCTION: Bálint's syndrome involves bilateral damage to the parieto-occipital area. The extent of the effect of unilateral damage on the Bálint's triad (oculomotor apraxia, optic ataxia, and simultanagnosia) remains unknown. METHODS: We examined a 63-year-old, right-handed woman who developed right hemianopia, oculomotor apraxia, optic ataxia, simultanagnosia, and hemispatial neglect (HSN) for the right after a cerebral infarction, with detailed neuropsychological tests, magnetic resonance imaging, and single photon emission computed tomography (SPECT). RESULTS: Neuropsychological examination showed that oculomotor apraxia, optic ataxia, and simultanagnosia were more pronounced in the right hemi-space, probably due to the limited eye movement in the right visual field, whereas HSN was restricted to the right hemi-space. Diffusion-weighted MR images revealed hyperintensity in the left parieto-temporo-occipital region, and several spotty areas of the bilateral frontal and parietal subcortical regions. SPECT revealed hypoperfusion in the left parieto-occipital region and frontal operculum and small areas of the right superior parietal lobule. CONCLUSIONS: The case suggests that asymmetric (more pronounced in the right hemi-space) oculomotor apraxia, optic ataxia, and simultanagnosia occur in an extensive lesion of the left parieto-occipital cortices. Although HSN is not a prerequisite for simultanagnosia, the coexistence of HSN aggravates simultanagnosia in the hemi-space opposite the lesion.

Anosognosia in mild Alzheimer's disease is correlated with not only neural dysfunction but also compensation.

BACKGROUND: Anosognosia in Alzheimer's disease (AD) is a complicated, non-unitary phenomenon. In a clinical setting, patients with mild AD often preserve their awareness partially. We hypothesized that compensation, as well as neural dysfunction, could be correlated with anosognosia in mild AD. METHODS: The severity of anosognosia was evaluated using the Anosognosia Questionnaire for Dementia in 37 subjects with mild AD or mild cognitive impairment due to AD. The subjects also underwent single-photon emission computed tomography with N-isopropyl-p-[123 I]iodoamphetamine. Correlation between the severity of anosognosia and perfusion was assessed, and anosognosia (+) and (-) groups were compared. RESULTS: The severity of anosognosia was relatively mild; the mean Anosognosia Questionnaire for Dementia score was 6.76 ± 14.16. Subjects were divided into two groups: anosognosia (+) (n = 11) and anosognosia (-) (n = 26). In the single-photon emission computed tomography data analysis, the severity of anosognosia was correlated with both lower regional cerebral blood flows of the right prefrontal cortex and higher regional cerebral blood flows of the parietal cortex, especially the left temporo-parietal junction. CONCLUSIONS: Our results suggest that anosognosia in mild AD could be correlated with compensation as well as neural dysfunction. We speculate that this compensation may be related to the retrieval of outdated autobiographical memory.

Modulation of somatoparaphrenia following left-hemisphere damage.

Somatoparaphrenic symptoms after left-hemisphere damage are rare. To verify the potential role of body-related sensory (proprioceptive, visual, and somatosensory) manipulation in patients experiencing sensations of hand disownership, the symptoms of a patient suffering from right-hand somatoparaphrenia were monitored and clinical and neuropsychological variables were controlled. Four types of manipulation were administered: changes in spatial position of the hand, multisensory stimulation, and self-observation using video or mirrors. Multisensory visuo-tactile stimulation was efficacious in terms of reducing somatoparaphrenia, and changes in the position of the hand produced some positive effects. Third-person perspective self-observation did not, however, result in any changes.

Tactually-related cognitive impairments: sharing of neural substrates across associative tactile agnosia, agraphesthesia, and kinesthetic reading difficulty.

INTRODUCTION: A precise understanding of the neural substrates underlying tactually-related cognitive impairments such as bilateral tactile agnosia, bilateral agraphesthesia, kinesthetic alexia and kinesthetic reading difficulty is currently incomplete. In particular, recent data have implicated a role for the lateral occipital tactile visual region, or LOtv, in tactile object naming (Amedi et al. Cerebral Cortex 2002). Thus, this study set out to examine the degree to which the LOtv may be involved in tactually-related cognitive impairments by examining two unique cases. METHODS: To assess whether LOtv or the visual word form area (VWFA) is involved in tactually-related cognitive impairments, the average activation point of LOtv and that of VWFA were placed on the single-photon emission computed tomography (SPECT) cerebral blood flow images of two patients: one with bilateral associative tactile agnosia, bilateral agraphesthesia, and ineffective kinesthetic reading, and the other with kinesthetic reading difficulty. RESULTS: The average LOtv coordinate was involved in the area of hypoperfusion in both patients, whereas that of VWFA was not included in any of the hypoperfused areas. CONCLUSIONS: The results support the view that interruption of LOtv or disconnection to LOtv and to VWFA may cause these tactually-related cognitive impairments. Further, bilateral associative tactile agnosia and bilateral agraphesthesia are attributable toward the damage of the occipital lobe, whereas unilateral or predominantly one-sided associative tactile agnosia and agraphesthesia are attributable toward the damage of the parietal lobe.

Case report of anosognosia for hemiplegia: A fMRI study.

OBJECTIVE: The aim of this study is to verify the functional activation in a patient with anosognosia for hemiplegia following left brain lesions. METHODS: We report a case of a 53-year-old right-handed female patient. She came to our rehabilitative unit with a diagnosis of an ischemic major stroke in the left internal carotid artery and important hemiplegia to the right side. She underwent functional magnetic resonance imaging (fMRI), during which she performed a motor imagery task. RESULTS: The fMRI assessment showed an ischemic lesion in the frontotemporal and insular left areas. In the fMRI experiment, we revealed activation of the residual neural patterns of both hemispheres. CONCLUSION: We underlined an interest in the compensation mechanism that involved neural networks near brain lesions and some areas of the contro-lesional hemisphere, suggesting that the synaptic plasticity permitted an intra and inter-hemispheric reorganization of the cerebral system.

Distinguishing transient from persistent tactile agnosia after partial anterior circulation infarcts - Behavioral and neuroimaging evidence for white matter disconnection.

From a cohort of 36 patients presenting apperceptive tactile agnosia after first cortical ischemic stroke, 14 showed temporary impairment at admission. A previous multi-voxel analysis of the cortical lesions, using as explanatory variable the course of tactile object recognition performance over the recovery period of 9 months, partitioned the cohort into three subgroups. Of the 14 patients constituting two of the subgroups, 7 recovered from their impairment whereas 7 did not. These two subgroups could not be distinguished at admission. The primary aim of the present study is to present two assessments that can do so. The first assessment comprises a pattern of behavioral measures, determined via principal component analysis, encoded in three tests: picking small objects, macrogeometrical discrimination and tactile object recognition. The receiver operating characteristic curve derived from permutation of the behavioral test scores yielded an 80% probability of correct identification of the patient subgroup and an 8% probability for false identification. As done with the permuted scores, the pattern could predict the persistence of affliction of new stroke patients with tactile agnosia. The second predictive assessment extends our previous evaluation of cortical MRI lesion maps to include subcortical regions. Confirming our previous study, the lesions of the persistently impaired subgroup disrupted significantly the anterior arcuatus fasciculus and associated superior longitudinal fasciculus III in the ipsilesional hemisphere, impeding reciprocal information transfer between supramarginal gyrus and both the ventral premotor cortex and Brodmann area 44. Due to the importance of interhemispheric information transfer in tactile agnosia, we performed a supplementary analysis of tactile object recognition scores. It showed that haptic information transfer from the non-affected to the affected hands in the persistent cases partly restored function during the nine months, possibly following restoration of functional interhemispheric haptic information transfer at the border of posterior corpus callosum and splenium. In conclusion, the combined findings of the cortical lesion at subarea PFt of the inferior parietal lobule and the associated subcortical tract lesions permit almost perfect prediction of persistent impairment of tactile object recognition. The study substantiates the need for combined analysis of both cortical lesions and white matter tract disconnections.

A Neural Substrate for Mirror Agnosia and Mirror Image Agnosia - Is it a Network disorder?

BACKGROUND: Reflected image processing is a unique brain function and its abnormalities result in problems of localizing, recognizing the images, and utilizing this information in everyday life. OBJECTIVES: The aim of this study was to characterize clinical and neuropsychological profiles and to identify the probable neural substrate for this phenomenon in major cognitive disorder. MATERIALS AND METHODS: We conducted a prospective study from February 2015 to May 2017 in patients with Major Cognitive Disorder (MCD, DSM-5 criteria). All patients were tested for problems in reflected image processing using the detailed protocol after ethical approval of the institute and consent. They also underwent a detailed neuropsychological evaluation, biochemical tests and neuroimaging (structural, diffusion, and resting-state functional MRI) as per established protocol. RESULTS: Of the 18 patients, 11 had mirror agnosia (MA), 5 had mirror image agnosia (MIA) and 2 had both. MRI of MA patients showed parietal atrophy and whereas diffuse pattern of atrophy was seen with MIA. In the MA group, the left superior longitudinal fasciculus showed significantly greater fractional anisotropy and the left angular gyrus showed increased functional connectivity with left anterior cingulate, left dorsolateral prefrontal and bilateral posterior cingulate regions. CONCLUSION: Mirror image processing defects were not related to the type of MCD, severity or pattern of neuropsychological dysfunction. There are structural and functional alterations in localized regions as well as both hemispheres. Therefore, it is more likely to be a network disorder, irrespective of the MCD type or severity.

The neuroanatomy of asomatognosia and somatoparaphrenia.

OBJECTIVES: Asomatognosia is broadly defined as unawareness of ownership of one's arm, while somatoparaphrenia is a subtype in which patients also display delusional misidentification and confabulation. Studies differ with regard to the underlying neuroanatomy of these syndromes. METHODS: Three groups of patients with right-hemisphere strokes and left hemiplegia were analysed: G1, asomatognosia+neglect; G2, non-asomatognosia+neglect; G3, hemiplegia only. The asomatognosic group was further subdivided into somatoparaphrenia (G1-SP: asomatognosia+delusions/confabulation) and simple asomatognosia (G1-SA; asomatognosia without delusions/confabulation). RESULTS: Patients with all forms of asomatognosia (G1) had larger lesions than non-asomatognosic patients in all sectors. While patients with or without asomatognosia had significant temporoparietal involvement, we found that the subset of patients with somatoparaphrenia had the largest lesions overall, and somatoparaphrenia cases had significantly more frontal involvement than patients with simple asomatognosia. All patients with asomotognosia (G1-SP and G1-SA) had significant medial frontal damage, suggesting that this region may play a role in the development of asomatognosia in general. Somatoparaphrenia cases also had greater orbitofrontal damage than simple asomatognosia cases, suggesting that the orbitofrontal lesion was critical in the development of somatoparaphrenia. CONCLUSIONS: Asomatognosia results from large lesions involving multiple--including temporoparietal--sectors, but the addition of medial frontal involvement appears important. The addition of orbitofrontal dysfunction distinguishes somatoparaphrenia from simple asomatognosia. The data indicate roles for the right medial and orbitofrontal regions in confabulation and self-related systems.

What are the neural correlates of meta-cognition and anosognosia in Alzheimer's disease? A systematic review.

Awareness of one's own cognitive processes (metacognition) or of one's own illness or deficits (anosognosia) can be impaired in people with Alzheimer's disease (AD). The neural correlates of anosognosia within AD remain inconclusive. Understanding anosognosia is of importance because of its impact on carer burden and increased institutionalization. A systematic review of structural and functional neuroimaging studies was conducted to identify specific brain regions associated with anosognosia within AD. Thirty-two studies were included in the systematic review. Reduced gray matter density, cerebral blood flow, and hypometabolism in 8 key regions were significantly associated with increased anosognosia scores in people with AD. The most frequently associated regions were the inferior frontal gyrus, anterior cingulate cortex, and medial temporal lobe. Other key regions include the superior frontal gyrus, medial frontal gyrus, orbitofrontal cortex, posterior cingulate cortex, and the insula. Identifying brain regions associated with anosognosia can aid understanding and identification of anosognosia in people with AD and potentially facilitate improvements in care.

Left Parietal Tumors Presenting with Smartphone Icon Visual Agnosia: Two Cases of a Modern Presentation of Gerstmann Syndrome.

BACKGROUND: Gerstmanns syndrome-a clinical constellation of left-right confusion, finger agnosia, agraphia, and acalculia-is frequently attributed to pathology in the dominant inferior parietal lobe or temporo-occipital region. However, these unique clinical findings are often accompanied by more subtle signs, including aphasias, neglect, and agnosias. Associative visual agnosia, in which a patient is able to accurately perceive and describe but not recognize an object or symbol, is a well-documented but infrequently observed clinical entity. CASE DESCRIPTION: Here we detail 2 unique cases of patients who presented with the inability to recognize and use smartphone application icons. Both were found to have left temporo-occipital tumors displacing the left temporo-parietooccipital cortex. CONCLUSIONS: In the era of pervasive technology, we emphasize that smartphone icon associative visual agnosias may be recognized by discerning physicians in the clinical diagnosis of dominant parietal lobe pathology.

fMRI of global visual perception in simultanagnosia.

The integration of visual elements into global perception seems to be implemented separately to single object perception. This assumption is supported by the existence of patients with simultanagnosia who can identify single objects but are incapable of integrating multiple visual items. We investigated a case of simultanagnosia due to posterior cortical atrophy without structural brain damage who demonstrated an incomplete simultanagnosia. The patient successfully recognized a global stimulus in one trial but failed to do so just a few seconds later. Using event-related fMRI, we contrasted post hoc selected trials of successful global perception with trials of global recognition failure. We found circumscribed clusters of activity at the right and left primary intermediate sulci and a bilateral cluster at the ventral precuneus. The integration of multiple visual elements resulting in a conscious perception of their gestalt seems to rely on these bilateral structures in the human lateral and medial inferior parietal cortex.

Late-onset Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Presenting With Auditory Agnosia.

INTRODUCTION: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder that usually presents in childhood. Patients can have a wide array of neurological symptoms when presenting with stroke-like episodes, and imaging characteristics during the episodes can overlap with different neurological disorders. CASE REPORT: A 61-year-old woman presented with communication difficulties consistent with auditory agnosia and was found to have bitemporal abnormalities on imaging that first raised the concern for herpes simplex virus encephalitis. Further work-up, in conjunction with the patient's past medical and family history, suggested a mitochondrial disorder. Mitochondrial full genome analysis revealed m.3243A>G variant in the MT-TL1 gene, with 6% heteroplasmy in blood leading to a diagnosis of MELAS. CONCLUSIONS: MELAS is a disorder with clinical variability. Neuroimaging studies during stroke-like episodes in MELAS can provide significant clues to the underlying disorder. Although patients typically present in childhood, the first stroke-like episode can occur later in life in some patients, potentially related to a lower heteroplasmy level.

Early prediction of long-term tactile object recognition performance after sensorimotor stroke.

Until now tactile agnosia has been reported only in small, but detailed cross-sectional case studies. Here we show that multi-voxel pattern analysis (MVPA) of early diffusion-weighted lesion maps can be used to accurately predict long-term recovery of tactile object recognition (TOR) in 35 subjects with varying hand skill impairment and associated specific daily activity limitation after cortical sensori-motor stroke. Multiple regression analysis revealed the essentially dysfunctional subprocesses for object recognition in the specifically impaired subjects, i.e., grasping as determined by a subtest of Jebsen Taylor hand function test, and perception of macrogeometrical object properties. The Gaussian process regression of MVPA represents a function that relates a selection of lesioned voxels as input variables to TOR performance scores as target variables. On the behavioural level, patients fell into three recovery subgroups, depending on TOR performance over the observation period. Only baseline motor hand skill and shape discrimination were significantly correlated with the TOR trajectories. To define functionally meaningful voxels, we combined information from MVPA of lesion maps and a priori knowledge of regions of interest derived from a data bank for shape recognition. A high significance for the predicted TOR performances over nine months could be verified by permutation tests, leading us to expect that the model generalises to larger patient cohorts with first cortical ischemic stroke. The lesion sites of the persistently impaired subjects exhibited an overlap with critical areas related to the MVPA prediction map in the cytoarchitectonic areas PFt of inferior parietal lobule and OP1 of parietal operculum which are associated with higher order sensory processing. This ultimate check corroborated the significance of the MVPA map for the prediction of tactile object recognition. The clinical implication of our study is that neuroimaging data acquired immediately after first stroke could facilitate individual forecasting of post-stroke recovery.

Correlation between anosognosia and regional cerebral blood flow in Alzheimer's disease.

The purpose of this study was to determine the brain regions associated with anosognosia in Alzheimer's disease (AD). Anosognosia for memory disturbance was assessed in 29 probable AD patients, based on the discrepancy between questionnaire scores of the patients and their caregivers. In I-123-IMP single photon emission computed tomography (SPECT), a significant association was found between anosognosia and decreased perfusion in the orbitofrontal cortex, using regression analysis. This result is consistent with the previous studies that have reported an association between frontal dysfunction and anosognosia, and further suggests that the orbitofrontal cortex specifically associates with anosognosia in AD within the frontal cortex.